Tumor-Infiltrating Lymphocytes and Perforation in Colon Cancer Predict Positive Response to 5-Fluorouracil Chemotherapy

School of Surgery and Pathology, University of Western Australia, Nedlands, Western Australia, Australia.
Clinical Cancer Research (Impact Factor: 8.72). 04/2008; 14(5):1413-7. DOI: 10.1158/1078-0432.CCR-07-1994
Source: PubMed


The major pathologic markers of prognosis in colorectal cancer include vascular invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall. Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated with good outcome independently of these established prognostic markers. The aim of the present study was to investigate the prognostic significance of TILs and other routinely reported pathologic features in colon cancer, particularly in relation to the use of adjuvant chemotherapy.
Pathologic markers, disease-specific survival, and the use of adjuvant chemotherapy were recorded in a retrospective, population-based series of 1,156 stage III colon cancer patients with a median follow-up time of 52 months.
In patients treated by surgery alone (n = 851), markers with significant prognostic value included poor histologic grade, T4 stage, N2 nodal status, vascular invasion, and perforation, but not the presence of TILs. In patients treated with 5-fluorouracil-based chemotherapy (n = 305), TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95% confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival (HR, 0.67; 95% confidence interval, 0.27-1.05; P = 0.16). Patients with TILs or perforation seemed to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients without these features (HR, 0.84 and 0.82, respectively).
The apparent survival advantage from 5-fluorouracil associated with TILs and perforation requires confirmation in prospective studies. Because the presence of TILs reflects an adaptive immune response and perforation is associated with inflammatory response, these results suggest that there may be interactions between the immune system and chemotherapy leading to improved survival of colon cancer patients.

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    • "TILs have been identified in various types of tumors, including lung cancer. Their existence has been found to be associated with decreased tumor progression (25), induction of responses to chemotherapy (26,27) and increased lifetime of patients (28). TILs derived from neonatal cord blood mononuclear cells induced marked human lung and cervical tumor remission in NOD/SCID mice, and the antitumor effect was accompanied with a high infiltration of CD3+ T cells in tumors and a marked induction of apoptotic cell death (25). "
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    ABSTRACT: Drug resistance and immune deficiency are important factors for the poor prognosis of lung carcinoma. The present study explored the possible protective effect of immune reconstitution from peripheral blood mononuclear cells (PBMCs) on multi-drug-resistant human lung carcinoma Am1010 cells in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The inoculated tumor fragments grew rapidly in the NOD/SCID mice. The growth was significantly inhibited by intraperitoneal injection of PBMCs. In the mice injected with PBMCs, numerous CD3(+) and CD8(+) cells, but less CD4(+) cells, were found in spleen and tumor tissues. These data suggest that PBMC transplantation inhibits lung carcinoma progression via the reconstitution of the immune system, particularly of cytotoxic T lymphocytes.
    Oncology letters 10/2014; 8(4):1638-1644. DOI:10.3892/ol.2014.2379 · 1.55 Impact Factor
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    • "Several biological mechanisms have been proposed to explain why 5-FU-based adjuvant chemotherapy fails to benefit patients with a defective MMR system. These include an antitumor immune response involving the lymphocytic infiltration characteristic of MSI-H tumors [22], which may be diminished by the immunosuppressive effects of chemotherapy. In vitro studies have also predicted a differential efficacy of 5-FU with respect to MMR status. "
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    ABSTRACT: The aim of this study was to investigate the clinicopathologic features of and the prognosis for colorectal cancers (CRCs) with microsatellite instabilities (MSIs). Between 2006 and 2009, genotyping was performed on 245 patients with stage II/III CRCs to establish the MSI status. The clinicopathologic differences and the prognostic value of MSI were analyzed. The median follow-up period was 38 months (range, 7-68 months). Of the total 245 patients, 20 (8.2%) had MSI-high (H) and 225 (91.8%) had MSI-low (L) or stable (S) CRCs. Adjuvant chemotherapies were performed on 101 stage II (87.8%) and 107 stage III patients (82.3%). Patients with MSI-H CRCs more frequently had a family history of colon cancer (10% vs. 2.7%, P = 0.003), more frequently had a cancer located at the proximal colon (90.0% vs. 19.1%, P < 0.0001), and more often showed a mucinous phenotype or poor differentiation (35.0% vs. 7.1%, P = 0.001). Despite less frequent lymph node metastasis (25% vs. 55.6%, P = 0.01), the number of retrieved lymph nodes was higher (26.3 ± 13.1 vs. 20.7 ± 1.2, P = 0.04) in the MSI-H group. The overall survival and the disease-free survival (DFS) did not differ with respect to MSI status. However, in the stage II subgroup, the DFS for patients with MSI-H CRCs was significantly worse (72.2% vs. 90.7%, P = 0.03). The multivariate analysis performed on this subgroup revealed that MSI-H was an independent poor prognostic factor (adjusted hazard ratio, 4.0; 95% confidence interval, 1.0-15.6, P = 0.046). MSI-H CRCs had distinct clinicopathologic features, and MSI-H was an independent poor prognostic factor in stage II CRCs. Considering the majority of stage II patients were administrated adjuvant chemotherapy, the efficacy of adjuvant chemotherapy for treating MSI CRCs might be different from that for treating MSI-L/S tumors.
    Annals of Coloproctology 02/2014; 30(1):28-34. DOI:10.3393/ac.2014.30.1.28
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    • "CIN+ CRCs, instead, exhibit reduced expression of cytotoxic T-cell markers and intratumoural density of Foxp3-positive regulatory T cells (Treg cells) [38– 43]. These observations would explain why MSI-H+ CRCs tend to be more immunogenic than CIN+ CRCs and suggest that a dense infiltration of CTLs within TME could effectively mediate tumour cells destruction by releasing their lytic components [39] [40] [41] [42] [43] [44] [45] [46]. Several studies have shown that MSI- H+ CRCs are associated with a better prognosis than CIN+ CRCs. "
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    ABSTRACT: Over the past decade, growing evidence indicates that the tumor microenvironment (TME) contributes with genomic/epigenomic aberrations of malignant cells to enhance cancer cells survival, invasion, and dissemination. Many factors, produced or de novo synthesized by immune, stromal, or malignant cells, acting in a paracrine and autocrine fashion, remodel TME and the adaptive immune response culminating in metastasis. Taking into account the recent accomplishments in the field of immune oncology and using metastatic colorectal cancer (mCRC) as a model, we propose that the evasion of the immune surveillance and metastatic spread can be achieved through a number of mechanisms that include (a) intrinsic plasticity and adaptability of immune and malignant cells to paracrine and autocrine stimuli or genotoxic stresses; (b) alteration of positional schemes of myeloid-lineage cells, produced by factors controlling the balance between tumour-suppressing and tumour-promoting activities; (c) acquisition by cancer cells of aberrant immune-phenotypic traits (NT5E/CD73, CD68, and CD163) that enhance the interactions among TME components through the production of immune-suppressive mediators. These properties may represent the driving force of metastatic progression and thus clinically exploitable for cancer prevention and therapy. In this review we summarize results and suggest new hypotheses that favour the growing impact of tumor-infiltrating immune cells on tumour progression, metastasis, and therapy resistance.
    Journal of Immunology Research 01/2014; 2014:686879. DOI:10.1155/2014/686879 · 2.93 Impact Factor
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